Women now constitute one of the fastest growing populations becoming infected with HIV. Drug use plays a major role in the spread of this disease in women: 46 percent of women's AIDS cases are directly attributable to injection drug use, vs. only 22 percent of cases in men. In addition, gender differences in response to psychostimulants (i.e., females are more sensitive to cocaine and amphetamines) have been reported both in animals and humans; however, the biological mechanisms which underlie these gender differences to HIV infection and psychostimulants remain for the most part, unexplained and undressed scientifically. The proposed program poses the major question: are biological gender differences n responsiveness to (repeated) cocaine predisposing females ot HIV-induced neurotoxicity? Our hypothesis is: Estrogens will act as protective agents fot he combined effects of repeated IV cocaine administration and gp120/tat neurotoxicity. First, we will determine whether steroid hormones are neuroprotective against the combined effects of gp120/tat and cocaine in cultured human fetal neurons. Second, we will determine whether estrogen regulate the expression of gender differences in response to HIV neurotoxicity in adulthood. Specifically, we will test the ability of estrogen to modulate gp120 and tat neurotoxicity in female animals chronically exposed to cocaine. We have successfully developed an innovative, technically simple, economical and practical on-tethered technique for repeatedly administering cocaine IV to freely moving group-housed, rats. Detailed pharmacokinetic analysis has demonstrated rapidly peaking cocaine levels following IV dosing in rats, which is similar to that observed in humans. Using this clinically relevant IV rodent dosing model, we will determine whether pharmacokinetic factors contribute to the increased sensitivity of female animals to the effects of nicotine. Third, using this clinically relevant IV cocaine rodent-dosing model, we will determine whether gp120 and tat produce dopaminergic neurotoxicity and receptor alterations in female animals following chronic cocaine. Our rodent model of IV cocaine, in combination with HIV protein neurotoxicity, is innovative and will be translational to the important woman's health issues of drug abuse and AIDS. The goal of this research is to provide potential insight into effective biologically-based gender-specific treatment strategies for HIV and cocaine addiction.